Thrombin stimulates insulin secretion via protease-activated receptor-3.
Thrombin stimulates insulin secretion via protease-activated receptor-3.
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DOI：
10.1080/19382014.2015.1118195
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发表时间：
2015
期刊：
影响因子：
2.2
通讯作者：
Rosengren AH
中科院分区：
文献类型：
--
作者：
Hänzelmann S;Wang J;Güney E;Tang Y;Zhang E;Axelsson AS;Nenonen H;Salehi AS;Wollheim CB;Zetterberg E;Berntorp E;Costa IG;Castelo R;Rosengren AH
2型糖尿病（T2D）的发病机制仍不明确。在这里，我们旨在通过分析人类胰岛基因共表达网络来探讨T2D的病理生理。使用部分相关网络，我们确定了一组共表达基因（“模块”），包括与糖化血红蛋白相关的F2RL2。F2Rl2是一种编码蛋白酶激活受体-3 （PAR3）的g蛋白偶联受体（GPCR）。PAR3被凝血酶切割，这暴露了一个6个氨基酸序列，作为一个“栓系配体”来调节细胞信号传导。我们通过静态胰岛素分泌测量、电容测量、糖尿病动物模型和患者样本的研究，表征了PAR3激活对胰岛素分泌的影响。我们证明凝血酶刺激胰岛素分泌，这种作用被一种阻断PAR3凝血酶切割位点的抗体所阻止。与PAR3拴系配体相对应的肽治疗刺激胰岛胰岛素分泌和单β细胞胞外分泌，其机制涉及磷脂酶C的激活和细胞内储存的Ca2+释放。此外，我们观察到，调节凝血酶生成的组织因子的表达在T2D供者的胰岛中增加，并与β细胞胞吐增强有关。最后，我们证明T2D患者凝血酶生成潜力与空腹胰岛素和胰岛素原指数升高有关。这些发现提供了高凝性和高胰岛素血症之间先前未被认识到的联系，并表明降低凝血酶活性或阻断PAR3裂解可能潜在地抵消胰岛素分泌过度，从而导致胰岛素抵抗和β细胞衰竭。
The disease mechanisms underlying type 2 diabetes (T2D) remain poorly defined. Here we aimed to explore the pathophysiology of T2D by analyzing gene co-expression networks in human islets. Using partial correlation networks we identified a group of co-expressed genes (‘module’) including F2RL2 that was associated with glycated hemoglobin. F2Rl2 is a G-protein-coupled receptor (GPCR) that encodes protease-activated receptor-3 (PAR3). PAR3 is cleaved by thrombin, which exposes a 6-amino acid sequence that acts as a ‘tethered ligand’ to regulate cellular signaling. We have characterized the effect of PAR3 activation on insulin secretion by static insulin secretion measurements, capacitance measurements, studies of diabetic animal models and patient samples. We demonstrate that thrombin stimulates insulin secretion, an effect that was prevented by an antibody that blocks the thrombin cleavage site of PAR3. Treatment with a peptide corresponding to the PAR3 tethered ligand stimulated islet insulin secretion and single β-cell exocytosis by a mechanism that involves activation of phospholipase C and Ca2+ release from intracellular stores. Moreover, we observed that the expression of tissue factor, which regulates thrombin generation, was increased in human islets from T2D donors and associated with enhanced β-cell exocytosis. Finally, we demonstrate that thrombin generation potential in patients with T2D was associated with increased fasting insulin and insulinogenic index. The findings provide a previously unrecognized link between hypercoagulability and hyperinsulinemia and suggest that reducing thrombin activity or blocking PAR3 cleavage could potentially counteract the exaggerated insulin secretion that drives insulin resistance and β-cell exhaustion in T2D.